Journal article
Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study
Human gene therapy, Vol.28(1), pp.99-111
01/01/2017
DOI: 10.1089/hum.2016.117
PMCID: PMC5278797
PMID: 27710144
Abstract
Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat ® ). Patients with advanced NVAMD were enrolled at three centers in the United States, and the study eye received a subretinal injection of 2.4 × 10 4 ( n = 3), 2.4 × 10 5 ( n = 3), or 8.0 × 10 5 transduction units (TU; n = 15). Each of the doses was well-tolerated with no dose-limiting toxicities. There was little or no ocular inflammation. There was one procedure-related serious adverse event (AE), a macular hole, which was managed without difficulty and resolved. There was a vector dose-related increase in aqueous humor levels of endostatin and angiostatin with high reproducibility among subjects within cohorts. Mean levels of endostatin and angiostatin peaked between 12 and 24 weeks after injection of 2.4 × 10 5 TU or 8.0 × 10 5 TU at 57–81 ng/mL for endostatin and 15–27 ng/mL for angiostatin, and remained stable through the last measurement at week 48. Long-term follow-up demonstrated expression was maintained at last measurement (2.5 years in eight subjects and >4 years in two subjects). Despite an apparent reduction in fluorescein angiographic leakage that broadly correlated with the expression levels in the majority of patients, only one subject showed convincing evidence of anti-permeability activity in these late-stage patients. There was no significant change in mean lesion size in subjects injected with 8.0 × 10 5 TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy.
Details
- Title: Subtitle
- Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study
- Creators
- Peter A Campochiaro - 1The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MarylandAndreas K Lauer - 2Casey Eye Institute, Oregon Health and Science University, Portland OregonElliott H Sohn - 3Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IowaTahreem A Mir - 1The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MarylandStuart Naylor - 4Formerly of Oxford BioMedica (UK) Ltd., Oxford, United KingdomMatthew C Anderton - 5Oxford BioMedica (UK) Ltd., Windrush Court, Oxford, United KingdomMichelle Kelleher - 5Oxford BioMedica (UK) Ltd., Windrush Court, Oxford, United KingdomRichard Harrop - 5Oxford BioMedica (UK) Ltd., Windrush Court, Oxford, United KingdomScott Ellis - 5Oxford BioMedica (UK) Ltd., Windrush Court, Oxford, United KingdomKyriacos A Mitrophanous - 5Oxford BioMedica (UK) Ltd., Windrush Court, Oxford, United Kingdom
- Resource Type
- Journal article
- Publication Details
- Human gene therapy, Vol.28(1), pp.99-111
- DOI
- 10.1089/hum.2016.117
- PMID
- 27710144
- PMCID
- PMC5278797
- NLM abbreviation
- Hum Gene Ther
- ISSN
- 1043-0342
- eISSN
- 1557-7422
- Publisher
- Mary Ann Liebert, Inc
- Language
- English
- Date published
- 01/01/2017
- Academic Unit
- Ophthalmology and Visual Sciences
- Record Identifier
- 9983979963102771
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